Schizophrenia is a common disease in the general population with 1% prevalence. Three classic genetic studies on family aggregation, monozygotic twins, and adopted children revealed that there is a strong genetic contribution to the etiology of schizophrenia. Several candidate susceptibility genes have been identified in the recent human linkage and genetic association studies. All candidate genes carry low risk ratios for the disease however, and few functional mutations have been identified. Therefore, it is difficult to study how the genetic mutation would contribute to the pathogenesis of schizophrenia in transgenic mouse models. However, there are a few well defined functional mutations identified with high penetrance in schizophrenia families. The studies on these genes with known functional mutations will provide valuable insights for our understanding of the underlying molecular mechanism for schizophrenia. Disrupted-in-schizophrenia (DISC1) was identified in a large Scottish schizophrenia family and constitutes a clear and compelling functional mutation with high penetrance. Our recent studies demonstrated that another gene, Boymaw, was also disrupted in the Scottish schizophrenia family and two fusion transcripts were formed between DISC1 and Boymaw genes. We hypothesize that these fusion transcripts give rise to chimeric proteins in neural circuitry relevant to schizophrenia. To test our hypothesis, we propose to create a humanized mouse line expressing both DISC1-Boymaw fusion transcripts. The successful development of a conditional knockin mouse line expressing both DISC1-Boymaw transcripts will be invaluable not only to study the molecular mechanism for the disease but also to explore both prevention and cure of behavioral abnormalities by correcting the genetic mutations (inducible Cre-LoxP system). Such mice can also be used to examine relationships between genetic vulnerability (fusion transcripts) and environmental insults relevant to schizophrenia and other neuropsychiatric disorders, such as stress, immune challenge, developmental insult, or epigenetic effects. These mice will play a crucial role in understanding where and how susceptibility genes affect specific neural substrates involved in the modulation of psychiatric-related endophenotypes. To initiate the investigation of this hypothesis, the following specific aims are proposed. R21 PHASE SPECIFIC AIMS Specific Aim 1: Generation of humanized mice harboring human DISC1-Boymaw fusion transcripts. R33 PHASE SPECIFIC AIMS Specific Aim 1: To test the hypothesis that expression of the DISC1-Boymaw fusion transcripts results in abnormal hippocampal development. Specific Aim 2: To test the hypothesis that expression of DISC1-Boymaw fusion transcripts produces functional impairments in schizophrenia-relevant behaviors. PUBLIC HEALTH RELEVANCE: The human DISC1 gene has been proposed to be one of the most compelling susceptibility genes for schizophrenia, a chronic, severe mental disorder imposing a high financial burden on the quality of life of the patients, their families and communities. Recently, the Boymaw gene, another gene involved in the DISC1 mutation, has been identified to form fusion transcripts with the DISC1 gene. Understanding of the effects of these fusion transcripts will help elucidate the molecular and neural pathways for the pathogenesis of schizophrenia, as well as improve diagnosis and guide the development of effective drug treatment with minimal side effects.